RC118 Combined With RC148 as First-Line Treatment for Claudin 18.2-Positive, HER2-Negative Advanced G/GEJ Adenocarcinoma

Inclusion Criteria:

1. Voluntarily consent to participate and sign the informed consent form.
2. Age ≥ 18 years.
3. Expected survival > 12 weeks.
4. ECOG performance status of 0 or 1.
5. Histologically confirmed unresectable locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma.
6. No prior systemic antitumor therapy for locally advanced or metastatic gastric cancer. If neoadjuvant or adjuvant therapy has been received, disease recurrence or metastasis must occur ≥ 6 months after the end of such therapy.
7. The participant agrees to provide adequate fresh tumor tissue samples or archival paraffin tissue samples collected within the previous 3 years for Claudin 18.2 expression testing. The Claudin 18.2 test result from the central laboratory shows positive Claudin 18.2 expression.
8. Have a local laboratory report confirming HER2 negativity; have a qualified PD-L1 expression test result from a local laboratory or central laboratory.
9. Have at least one measurable lesion per RECIST v1.1.
10. Adequate bone marrow, hepatic and renal function.
11. Male and female participants of reproductive potential must use medically acceptable contraceptive measures from the signing of informed consent until 12 months after the last study treatment. Female participants of reproductive potential must have a negative serum pregnancy test within 7 days before the first dose of study treatment, and agree not to breastfeed or donate oocytes from signing informed consent until 12 months after the last study treatment. Male participants must agree not to donate sperm from signing informed consent until 12 months after the last study treatment.
12. Able to understand the study requirements, and be willing and able to comply with study and follow-up procedures.

Exclusion Criteria:

1. Prior receipt of any antibody drug conjugate, Claudin 18.2 targeted therapy, or concurrent antitumor therapy targeting vascular endothelial growth factor / vascular endothelial growth factor receptor and PD 1/PD L1.
2. Received palliative therapy for localized lesions within 2 weeks prior to randomization, or radiotherapy to the primary gastric lesion within 4 weeks prior to randomization.
3. Received traditional Chinese medicines with antitumor indications, or chemical drugs or biological products with immunomodulatory effects within 2 weeks prior to randomization.
4. Participated in another drug clinical trial and received investigational product within 4 weeks prior to randomization.
5. Underwent major surgery or tumor interventional therapy within 4 weeks prior to randomization, with incomplete recovery, or major surgery anticipated during study treatment.
6. Received live vaccines within 4 weeks prior to randomization or planned to receive any live vaccine during the study.
7. Systemic treatment with corticosteroids or other immunosuppressive agents, either ongoing use or requiring chronic use, within 2 weeks prior to randomization.
8. Presence of leptomeningeal metastasis, spinal cord compression or brainstem metastasis; symptomatic brain metastasis; untreated brain metastasis; symptomatic treatment such as corticosteroids for brain metastasis within 4 weeks prior to randomization; radiotherapy and/or surgery for brain metastasis within 4 weeks prior to randomization; progression of brain metastasis during or after local therapy.
9. Bone metastases with risk of paraplegia.
10. Per CTCAE Version 6.0: peripheral neuropathy ≥ Grade 2; residual toxicity from prior antitumor therapy ≥ Grade 2.
11. Clinically significant bleeding events or bleeding diathesis within 2 months prior to randomization.
12. Severe gastrointestinal dysfunction that may affect drug intake, transit or absorption; significant malnutrition.
13. History of gastrointestinal perforation or fistula, bowel obstruction, inflammatory bowel disease or bowel resection within 6 months prior to randomization.
14. Clinically symptomatic third space effusion requiring intervention within 2 weeks prior to randomization.
15. Active autoimmune disease requiring systemic therapy within 2 years prior to randomization.
16. History of other acquired or congenital immunodeficiency disorders, allogeneic hematopoietic stem cell transplantation or solid organ transplantation.
17. Active or uncontrolled infection within 2 weeks prior to randomization.
18. Severe or inadequately controlled systemic disease.
19. Diagnosis of interstitial lung disease (ILD); or moderate or worse impairment of pulmonary function.
20. History of active or severe cardiac disease.
21. Severe arterial/venous thromboembolic events, or cerebrovascular accidents within 6 months prior to randomization.
22. History of severe coagulopathy, and receiving anticoagulants for therapeutic purposes (prophylactic anticoagulation is excluded).
23. Concurrent second primary malignancy.
24. Hypersensitivity or intolerance to known components of the investigational product or analogous agents.
25. Active infectious disease.
26. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
27. Pregnant or lactating women.
28. Any other disease, metabolic abnormality, abnormal physical finding or laboratory abnormality that raises suspicion of a condition rendering the participant unsuitable for the investigational product, that would confound the interpretation of study results, or that places the participant at substantial risk.
29. Psychiatric disorder, history of substance abuse or social circumstances that may compromise study compliance. Participants judged to have inadequate adherence to this clinical trial, or with other factors making participation inappropriate.